Adhesions are among the most frequent complications after interventions in the abdominal and pelvic region. Adhesions are fibrous bands which generally form within the first seven days after an operation, in the course of the healing process. They cause tissues and organs which are normally separated from one another to grow together, which can give rise to a multiplicity of complications such as, for example, chronic pain, infertility or a life-treating intestinal occlusion. Products able to reduce the formation of adhesions have been developed in recent years to avoid such complications. Success has so far been limited, however.
Methods of preventing adhesions are peritoneal cavity lavage; the use of pharmacologically active agents such as anti-inflammatories or fibrinolytics; and also the application of mechanical barriers to separate the tissue. Adhesion barriers consist of an inert or absorbable material which is applied to the organs in question. Research has been done on a multiplicity of materials such as polysaccharides (U.S. Pat. Nos. 4,886,787, 5,356,883), hyaluronic acid U.S. Pat. Nos. 4,141,973, 5,246,698), alginates (U.S. Pat. No. 5,266,326), chitin (U.S. 5,093,319), chitosan (U.S. Pat. Nos. 4,532,134, 5,679,658), xanthan (U.S. Pat. No. 4,994,277), dextran (U.S. Pat No. 5,605,938), cellulose and derivatives thereof (Journal of spinal disorders & techniques (2006), 19(4), 270-5), human serum albumin (U.S. Pat. No. 5,583,114), collagen (US 2005175659), glucosamine (U.S. Pat. No. 5,462,976), polyoxyalkylene copolymers (U.S. Pat. Nos. 4,911,926, 5,366,735, 5,135,751, 5,681,576), polyester (U.S. Pat. Nos. 5,612,052, 6,136,333), etc. A large proportion of these materials have not been commercialized for lack of efficacy, lack of bioabsorbability or because of interactions with the wound-healing process.
Commercially available products in membrane form such as INTERCEED™ (Johnson & Johnson), SEPRAFILM™ (Genzyme Corp.) and REPEL-CV™ (Life Medical Corp.), are absorbed within 28 days. However, since the barriers are laid onto the organ in question, there is a risk of slippage.
Barriers which like the hyaluronic acid derivative SEPRACOAT™ (GenzymeCorp.) and LUBRICOAT™ (Lifecore Biomedical Inc.) are applied as a liquid are often too quickly degraded by the body, limiting their barrier effect. In addition, there is a risk of migration and hence of no protective effect at all.
Hydrogels are water-containing polymers whose chains are linked covalently to form a three-dimensional network. In water, they swell rapidly and with a substantial increase in volume. Owing to their high water content, they are being investigated for use as adhesion barriers. As well as the hydrogels based on natural polysaccharides (alginates, hyaluronic acid) it is in particular hydrophilic polyethylene glycol-based systems (US 2005266086, DE-A 69929278, U.S. Pat. Nos. 7,025,990, 6,514,534, US 2003/0077242), such as the commercially available SPRAYGEL™ (Confluent Surgical), which have been the subject of intensive research. Disadvantages found include the occasionally excessive rate of degradation and the acidity of the degradation products of lactic acid-based polyesters. As well as the polyethylene glycol-based hydrogel formation, there are frequent mentions (WO 0009087, US 20030077242, US 20050271727) of the redox-initiated free-radical polymerization. Redox initiators used include ascorbic acid and peroxides. As well as possible tissue irritation, one of the problems which arises is the aqueous consistency of the two reactants which is responsible for the absence of bonding to the organ in question.
Isocyanate-capped polymers such as polyester- and polyether-urethanes are described in US 2004/0068078 and WO 2004/021983 for uses including as postoperative adhesion barriers. Isocyanates used are preferably TDI (toluylene diisocyanate) and IPDI (isophorone diisocyanate), the prepolymers containing 0.05 to 1 mEq of low molecular weight polyisocyanaes such as monomeric TDI to promote adherence to the tissue being treated. In the presence of significant biological fluid, or in adherence to certain types of tissue, greater amounts thereof should preferably be present. Adherence develops inter alia through reaction of the isocyanate with the tissue. However, monomeric isocyanates, as well as tissue irritation, are known to lead to a sensitization and hence to allergic reactions. The reaction rate of the prepolymer on the tissue is substantially slowed when aliphatic isocyanates such as HDI are used, and therefore such a system is not practicable for clinical use.
U.S. Pat. No. 7,129,300 describes the production of absorbable 2-component systems consisting of a polyethylene oxide having two or more amine substituents and a biodegradable diisocyanate or an isocyanate-capped polyethylene oxide with an absorbable diamine.
WO 2006/010278 describes the production and use of polyurethane prepolymers and polyurethane acrylates based on aliphatic isocyanates such as HDI. Chain extenders (curatives) used are low molecular weight diols, diamines, triols, triamines or oligomers and also physiologically active compounds. Organic zinc, tin, magnesium and iron compounds are used as a catalyst. The invention is useable inter alia as an adhesion barrier but also for various implants. However, the use of a catalyst generally leads to a substantial acceleration in the rate of curing of the polymer and hence to an increased evolution of heat. Usefulness for internal organs is limited as a result.
EP-A 1719530 describes the use of isocyanate-capped polyester macromers based on aliphatic dicarboxylic acids and dihydroxy components such as polyalkylene oxides or polyethylene glycols. Aromatic, aliphatic and alicyclic isocyanates are described as possible isocyanates. Prepolymers formed from aromatics-based isocyanates such as TDI (as recited in the examples) have a reported crosslinking time on tissue of 1-10 min. However, the use of aromatics-based isocyanates in the body where, like the adhesion barriers, the product is fully degraded must be considered problematical because of the cleavage products which form. Systems based on aliphatic isocyanates are known from experience to have insufficient reactivity and hence too slow a cure time for practicable use in vivo. In addition, the viscosities of the compounds recited in EP-A 1719530 are too high at an average of 60 000 mPas for application, and therefore a solvent has to be used.
WO 2007/067624 describes a bioabsorbable 2-component system consisting of an isocyanate prepolymer based on glycolide, lactide, ε-caprolactone, p-dioxanone, trimethyl carbonate and polyalkylene oxide (for example polyethylene glycols). The second component used is a polyamine. On application of the two components to tissue a gel is formed that is useful as an adhesive or as an adhesion barrier. However, the prepolymers have an extremely high viscosity and therefore are difficult to apply without added solvent. Possible solvents mentioned include water, alcohols and ketones. Hydroxyl-containing solvents, however, present the problem of rapid reaction with the prepolymer, so that there is a risk of gelling. Processing time, moreover, can become extremely rapid and thereby make processing problematical. The use of solvents in vivo must generally in most cases be considered problematical on account of possible cytotoxicity and also interaction with the tissue.
That aspartic esters are suitable in principle for crosslinking prepolymers is known in the prior art in the context of surface coatings and described in DE-A 10246708 or EP-A 1081171.
European patent application No. 07021764.1, unpublished at the priority date of the present invention, already describes wound adhesives based on a combination of hydrophilic polyisocyanate prepolymers and aspartates as hardeners. The prepolymers are based on polyether polyols and therefore are not biodegradable within 6 to 12 months. In addition, the systems described are strong adhesives and therefore unsuitable for use as an adhesion barrier.